My objective is to combine my expertise in the biochemical basis of diabetic complications with my clinical research to develop new approaches for understanding the pathogenesis of this devastating cluster of diseases. My career has had several phases, including basic science, clinical endocrinologist, and educator, but over the past 10 years I have become fully committed to the continued development of a strong clinical research program. I believe that such a program could be a model for those considering a career in clinical investigation. Funding is being sought through this K-24 program to continue this transition and achieve blocks of protected time to focus on my research and develop a mentoring program for the training of clinical investigators. Over the longer term, my objectives are to create a stable and productive research program which will span the hitherto neglected gap between clinical and basic science and provide a fertile training ground for new investigators. The research and mentoring will take place at Dartmouth Medical School (DMS) and its two major clinical facilities, the Dartmouth-Hitchcock Medical Center (DHMC) and the White River Junction Veterans Hospital (VAH). This institution offers a rich milieu for one seeking well educated and highly motivated trainees, and has all of the required facilities for clinical research program. I have carefully prepared a comprehensive mentoring program which can be immediately implemented if this award is granted. This program is designed to give the trainees proficiency in the planning, execution and completion of study projects that provide a model combining powerful analytical tools with carefully selected clinical populations to solve important diabetes related questions. Over the 5 years of the granting period I propose to spend my time on three concurrent projects evaluating the role of nonenzymatic glycation, dicarbonyls, and AGEs in the pathogenesis of diabetic complications. The projects currently in progress or planned include. a. Effect and mechanism of action of binding agents on the production, detoxification, and scavenging of alpha-dicarbonyls and the progression of diabetic macrovascular complications, b. The role of post-prandial hyperglycemia on alpha-dicarbonyls, tissue glycation, and diabetic macrovascular complications. c. Methylglyoxal production and the role of Fructosamine 3 Kinase (FN3K) deglycation in the control of glucose-mediated nonenzymatic glycation and predisposition to diabetic nephropathy . Additional clinical projects will be added as selected basic research projects in my laboratory "mature" and as other study populations present improved models to test our hypotheses. These exciting research projects, and new ones on the horizon, combined with the proposed mentoring/training program offers real opportunities of attracting and rewarding a new generation of clinical investigators.